JP2009519907A - Chemical derivatives of jasmonate, pharmaceutical compositions and methods for their use - Google Patents

Abstract

  The present invention relates to novel jasmonate derivatives, methods for their preparation, pharmaceutical compositions containing such compounds, and methods of using these compounds and compositions as chemotherapeutic agents, particularly for the prevention and treatment of cancer.

Description

TECHNICAL FIELD The present invention relates to jasmonate derivative compounds, methods for their preparation, pharmaceutical compositions containing such compounds, and treatment of these compounds and compositions, particularly cancer (especially mammals, especially humans). It relates to the field of use as a chemotherapeutic agent.

BACKGROUND OF THE INVENTION Jasmonates are plant stress hormones that are derived from linolenic acid by the octadecanoid pathway and are found in trace amounts in many edible plants. Stress hormones such as jasmonates develop in plants and are released during stresses such as extreme UV radiation, osmotic shock, heat shock and pathogen attack, initiating various cascades that end with appropriate responses. Examples of jasmonate compounds are jasmonic acid (which is crucial for intracellular signaling in response to injury) and methyl jasmonate (which is a proteinase that accumulates at low concentrations in response to trauma or pathogen attack) Cause induction of inhibitors). The use of jasmonate for the treatment of mammalian cancer is disclosed in US Pat. No. 6,469,061, the contents of which are incorporated by reference in their entirety. In US Pat. No. 6,469,061, jasmonate was shown to be a direct cytotoxic for various types of human cancer cells derived from breast, prostate, skin and blood cancers. Jasmonates caused death of human leukemia Molt-4 cells, but they did not impair normal lymphocytes.

  In US Pat. No. 6,469,061, one particular jasmonate compound, methyl jasmonate, was shown to be effective in preventing lymphoma progression in mice. In addition, “plant stress hormones suppress the proliferation of human cancer cells and induce apoptosis in human cancer cells” (Fingrut, O. and E.e. 60, L., E. and L. 16). 616 (2002)).

  Subsequent data collected similarly showed that jasmonate does not impair healthy red blood cells (see WO 02/080890, the contents of which are incorporated by reference in their entirety).

  PCT International Patent Publication WO 2005/054172 discloses novel halogenated jasmonate derivatives, pharmaceutical compositions containing the derivatives, and their use to attenuate cancer cell growth and treat cancer.

  Jasmonic acid bonded to an amino acid through a carboxyl group is found in nature (Plant Hormones, edited by Davids PJ, Kluwer Academic Publishers, London, 2004, 618, 620). Several jasmonic acid-amino acid conjugates were prepared synthetically. These amino acids include glycine, alanine, valine, leucine and isoleucine (Jikumaru Y. et al. Biosci. Biotechnol. Biochem. 68, 1461-1466 2004).

  Because of the pharmacological activity of jasmonate compounds, they have become attractive candidates as therapeutic agents for the treatment of cancer. Only a very small number of jasmonate derivatives have been reported in the art (eg Ishii et al., Leukemia, 1-7 (2004); Seto et al. Biochem. Biosc. & Biotech. 63 (2), (1999); see Hossain et al. Biochem. Biosci. & Biotech. 68 (9), 1842 (2004)). There is a need to develop jasmonate derivative compounds that are potent chemotherapeutic agents with a high degree of specificity for malignant cells.

SUMMARY OF THE INVENTION The present invention relates to novel jasmonate derivative compounds.

  Preferred jasmonate derivatives are represented by the general structure of Formula I. Other preferred jasmonate derivatives are the specific derivatives represented by structures 1-11. Some of these compounds are significantly more potent than the compounds disclosed in US Pat. No. 6,469,061 and WO2005 / 054172. These novel derivatives exert selective cytotoxicity on cancerous cells while leaving normal cells intact. Thus, the compounds of the present invention are useful for inhibiting cancer cell growth and treating various cancers.

式中、
Ａは、
ａ）ＣＯＲ^１、
ｂ）Ｏ−ＣＯＲ^１０、及び
ｃ）ＯＲ^１１
からなる群から選択され；
Ｒ^１は、
ａ）ヘテロアリールオキシ、
ｂ）−Ｏ［（ＣＨ_２）_ｐＯ）］_ｍ−Ｒ^１２、
ｃ）次の式の基

からなる群から選択され、また
ｄ）Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６及びＲ^７の少なくとも１つがハロアルキルである場合、或いは、Ｒ^５及びＲ^６が、これらが結合している炭素と一緒にＣ_３〜Ｃ_８シクロアルキル、又はハロにより置換されたＣ_３〜Ｃ_８シクロアルキルを形成している場合、Ｒ^１はさらに、水素又は非置換若しくは置換Ｃ_１〜Ｃ_１２アルキルを表すことができ；
Ｒ^２は、水素、非置換又は置換Ｃ_１〜Ｃ_１２アルキル、非置換又は置換Ｃ_３〜Ｃ_８シクロアルキル、非置換又は置換アリール、非置換又は置換ヘテロアリール、ＯＲ^８、オキソ及びＮＲ^９ａＲ^９ｂからなる群から選択され；
Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６及びＲ^７は、それぞれ独立に、水素、ハロゲン、非置換又は置換Ｃ_１〜Ｃ_１２アルキル、非置換又は置換Ｃ_１〜Ｃ_１２ハロアルキル、非置換又は置換Ｃ_３〜Ｃ_８シクロアルキル、非置換又は置換アリール、非置換又は置換ヘテロアリール、ＯＲ^８、及びＮＲ^９ａＲ^９ｂからなる群から選択されるか、
或いは、Ｒ^５及びＲ^６は、これらが結合している炭素と一緒にＣ_３〜Ｃ_８シクロアルキル、又はハロにより置換されたＣ_３〜Ｃ_８シクロアルキルを形成しているか、
或いは、Ｒ^５及びＲ^６の一方は酸素原子を表し、この酸素原子がＣ_６に結合してそれぞれ６員又は５員の酸素含有複素環を形成しており；
Ｃ_９とＣ_１０との間の結合は単結合又は二重結合であってよく；
Ｒ^８、Ｒ^９ａ及びＲ^９ｂは、それぞれ独立に、水素、非置換又は置換Ｃ_１〜Ｃ_１２アルキル、非置換又は置換Ｃ_３〜Ｃ_８シクロアルキル、非置換又は置換アリール、非置換又は置換ヘテロアリール、グルコシルからなる群から選択されるか、或いは、Ｒ^９ａ及びＲ^９ｂは、これらが結合している窒素と一緒に、非置換若しくは置換複素環又は複素芳香族環（Ｏ、Ｎ及びＳから選択される１つ又は複数のさらなるヘテロ原子を場合によって含む）を形成していてもよく；
Ｒ^１０は、水素、非置換又は置換Ｃ_１〜Ｃ_１２アルキル、非置換又は置換Ｃ_３〜Ｃ_８シクロアルキル、非置換又は置換アリール、及び非置換又は置換ヘテロアリールからなる群から選択され；
Ｒ^１１及びＲ^１２は、それぞれ独立に、水素又はヒドロキシ保護基であり；
Ｒ^１３は、カルボキシ保護基であり；
Ｒ^１４は、天然又は非天然のアミノ酸残基であり；
ｎは、０、１及び２から選択され；
ｍは、１から２０の整数であり；また
ｐは、１から１２の整数である。 In one embodiment, the jasmonate derivative is represented by the structure of formula I, including salts, hydrates, solvates, polymorphs, optical isomers, geometric isomers, enantiomers, diastereomers, and mixtures thereof. .

Where
A is
a) COR ¹ ,
b) O-COR ¹⁰ and c) OR ¹¹
Selected from the group consisting of;
R ¹ is
a) heteroaryloxy,
_{b) -O [(CH 2)} p O)] m -R 12,
c) group of formula

D) when at least one of R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is haloalkyl, or R ⁵ and R ⁶ are attached to the carbon to which they are attached together _C 3 -C ₈ cycloalkyl, or forming a _C 3 -C ₈ cycloalkyl substituted with halo, ^{R 1} is further represent a hydrogen or an unsubstituted or substituted _C 1 _{-C 12} alkyl Can do;
R ² is hydrogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, OR ⁸ , oxo and NR ^9a R Selected from the group consisting of ^9b ;
R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₁ -C ₁₂ haloalkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or is selected from the group consisting of oR ^8, and ^NR 9a ^{R 9b,}
Alternatively, R ⁵ and R ⁶ together with the carbon to which they are attached form a C ₃ -C ₈ cycloalkyl, or a C ₃ -C ₈ cycloalkyl substituted with halo,
Alternatively, one of R ⁵ and R ⁶ represents an oxygen atom, and this oxygen atom is bonded to C ₆ to form a 6-membered or 5-membered oxygen-containing heterocyclic ring, respectively;
The bond between C ₉ and C ₁₀ may be a single bond or a double bond;
R ⁸ , R ^9a and R ^9b are each independently hydrogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted hetero R ^9a and R ^9b are selected from the group consisting of aryl, glucosyl, or together with the nitrogen to which they are attached, unsubstituted or substituted heterocycles or heteroaromatic rings (from O, N and S) Optionally comprising one or more additional heteroatoms selected);
R ¹⁰ is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
R ¹¹ and R ¹² are each independently hydrogen or a hydroxy protecting group;
R ¹³ is a carboxy protecting group;
R ¹⁴ is a natural or non-natural amino acid residue;
n is selected from 0, 1 and 2;
m is an integer from 1 to 20; and p is an integer from 1 to 12.

In one currently preferred embodiment, the group A of formula I is COR ¹ . In one embodiment, R ¹ is heteroaryloxy, preferably quinolinyloxy. In another embodiment, R ¹ is a polyoxyalkylene represented by the structure, —O [(CH ₂ ) _p O)] _m —R ¹² , eg, the structure, —O (CH ₂ —CH ₂ —O) _m -(M is an integer of 1 to 20). The presently preferred value of m is 4. The group R ¹² represents hydrogen or a hydroxy protecting group such as a trialkylsilylhydroxy protecting group.

In another embodiment, R ¹ is a group of the formula

The group R ¹³ is any carboxy protecting group, for example methyl, which together can define a methyl ester group. The group R ¹⁴ represents the residue of any natural or unnatural amino acid. The presently preferred amino acid is leucine. However, any other natural or unnatural amino acid as defined herein and known to those skilled in the art can be incorporated into the jasmonate-amino acid derivatives of the present invention.

In another currently preferred embodiment, the group A of formula I is O-COR ¹⁰ and R ¹⁰ is unsubstituted or substituted C ₁ -C ₁₂ alkyl, such as methyl. In yet another presently preferred embodiment, group A of formula I is OR ¹¹ and R ¹¹ is hydrogen or a hydroxy protecting group such as a trialkylsilylhydroxy protecting group.

In one presently preferred embodiment, R ² of formula (I) is oxo (═O). In another currently preferred embodiment, R ² of formula I is OR ⁸ and R ⁸ is unsubstituted or substituted C ₁ -C ₁₂ alkyl, such as methyl.

In one presently preferred embodiment, R ⁵ and R ⁶ are unsubstituted C ₃ -C ₈ cycloalkyl, or one or more halogens, together with the carbon to which they are attached (ie, C ₉ and C ₁₀ ). form a C ₃ -C ₈ cycloalkyl substituted by atoms. In one particular embodiment, R ⁵ and R ⁶ together represent one C (Hal) ₂ group (Hal is halogen), together with C ₉ and C ₁₀ , a halo-substituted cyclopropyl group Determine.

In another embodiment, each of R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is hydrogen. In another embodiment, the bond between C ₉ and C ₁₀ is a double bond, and each of R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is hydrogen. In yet another embodiment, the bond between C ₉ and C ₁₀ is a single bond and each of R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is hydrogen. In still another embodiment, R ⁶ represents an oxygen atom, and this oxygen atom is bonded to C ₆ to form an oxygen-containing 5-membered heterocycle.

Specific examples of compounds of formula I include, but are not limited to:

本明細書において示されるように、前記化合物は、正常な細胞にはほとんど作用を及ぼさず、癌細胞に対して選択的細胞毒性を示す、非常に効力が高く選択的な細胞毒性作用剤であることが、予想外に見出された。このため、化合物１１は、米国特許第６４６９０６１号に開示されているジャスモネートグルコシル誘導体に比べて驚くほど優れた性質を有する。 In yet another aspect, the present invention provides a jasmonate derivative represented by the structure of Formula 11 (salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, and the like) A mixture of

As shown herein, the compound is a highly potent and selective cytotoxic agent that has little effect on normal cells and exhibits selective cytotoxicity against cancer cells. It was discovered unexpectedly. For this reason, Compound 11 has surprisingly superior properties compared to the jasmonate glucosyl derivative disclosed in US Pat. No. 6,469,061.

  The present invention also provides a pharmaceutically acceptable carrier and, as an active ingredient, one of the compounds of the present invention represented by any of the above general formula I or any of the specific compounds of formulas 1-11 or Also contemplated are pharmaceutical compositions comprising a plurality.

  The pharmaceutical composition of the present invention may be in any form known in the art, for example, for oral administration (eg, solution, suspension, syrup, emulsion, dispersion, suspension, tablet, round Pills, capsules, pellets, granules and powders), parenteral administration (eg intravenous, intramuscular, intraarterial, transdermal, subcutaneous or intraperitoneal), topical administration (eg ointment, gel, cream), It can be provided as a form suitable for administration by inhalation or suppository. Preferably, in the pharmaceutical composition of the present invention, the active ingredient is dissolved in any acceptable lipid carrier.

  Further in accordance with a preferred embodiment of the present invention the jasmonate derivative is administered with at least one other chemotherapeutic agent. The jasmonate derivative and the at least one chemotherapeutic agent may be administered simultaneously (as the same or separate dosage forms) or they may be administered sequentially in any order.

  The present invention further includes a method of inhibiting cancer cell growth, comprising contacting a cancer cell with a therapeutically effective amount of a compound of general formula I or any of formulas 1-11 described herein. provide. In some embodiments, the compound is administered as a pharmaceutical composition.

  Furthermore, the present invention provides a method for the treatment of cancer in a subject, either by administering to the subject a therapeutically effective amount of a compound of the invention described herein. Preferably, the compound is one or more of the compounds represented by any of the general formula I or any of the specific formulas 1-11. In some embodiments, the compound is administered as a pharmaceutical composition. In one aspect, the subject is a mammal, preferably a human.

  Furthermore, the present invention relates to compounds of any of formulas I, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 according to the present invention in the preparation of therapeutic agents useful for the treatment of cancer. About the use of.

  The compounds of the present invention are active against a wide range of cancers, including carcinomas, sarcomas, myelomas, leukemias, lymphomas and mixed type tumors. Specific classes of tumors that are amenable to treatment include lymphoproliferative disease, breast cancer, ovarian cancer, prostate cancer, cervical cancer, endometrial cancer, bone cancer, liver cancer, stomach cancer, colon cancer. Pancreatic cancer, thyroid cancer, head and neck cancer, central nervous system cancer, peripheral nervous system cancer, skin cancer, kidney cancer, and all these metastases. Specific types of tumors suitable for treatment include hepatocellular carcinoma, liver cancer, hepatoblastoma, rhabdomyosarcoma, esophageal cancer, thyroid cancer, ganglioblastoma, fibrosarcoma, myxosarcoma, liposarcoma, cartilage Sarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, Ewing tumor, leiomyosarcoma, rhabdotheliosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, melanoma, squamous epithelium Cancer, basal cell carcinoma, adenocarcinoma (highly differentiated, moderately differentiated, poorly differentiated or undifferentiated), renal cell carcinoma, adrenal carcinoma, hypernephroid adenocarcinomas, bile duct cancer, choriocarcinoma, seminoma, fetal Cancer, Wilms tumor, testicular tumor, lung cancer (including small cell, non-small cell and large cell lung cancer), bladder cancer, glioma, astrocytoma, medulloblast Tumor, craniopharyngioma, ependymoma, pineal gland, retinoblastoma, neuroblastoma, colon cancer, rectal cancer, hematopoietic malignant tumor (acute myelogenous leukemia), acute bone marrow All, including acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, mast cell leukemia, multiple myeloma, spinal cord lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma Types of leukemia and lymphoma).

  According to a particular embodiment, the cancer to be treated is prostate cancer, breast cancer, skin cancer, colon cancer, lung cancer, pancreatic cancer, lymphoma, leukemia, myeloma, head and neck cancer, kidney cancer, ovarian cancer, bone cancer, liver Selected from the group consisting of cancer or thyroid cancer. In exemplary embodiments, the cancer to be treated is selected from breast cancer, kidney cancer, gastric cancer, leukemia (including lymphoblastic leukemia), lung cancer, melanoma and colon cancer.

  The jasmonate derivatives of the present invention are significantly more potent than the compounds disclosed in US Pat. No. 6,469,061 and WO 2005/054172. They exhibit an unexpected cytotoxic effect with a high degree of specificity for malignant cells.

  Further aspects and the full scope of applicability of the present invention will become apparent from the detailed description provided hereinafter. However, while the detailed description and specific examples illustrate preferred embodiments of the present invention, various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from the detailed description. It should be understood that this is given for illustrative purposes only.

Detailed Description of the Invention The present invention relates to novel jasmonate derivative compounds. Preferred jasmonate derivatives are represented by the general structure of Formula I. Another preferred jasmonate derivative is a specific derivative represented by structures 1-11. Some of these compounds are significantly more potent than compounds disclosed in the art and exert selective cytotoxicity on cancerous cells (eg, lymphocytes, tumor cells and breast cancer cells) while being normal. It has very little effect on the cells. Thus, the compounds of the present invention are useful for inhibiting cancer cell growth and treating various cancers.

式中、
Ａは、
ａ）ＣＯＲ^１、
ｂ）Ｏ−ＣＯＲ^１０、及び
ｃ）ＯＲ^１１
からなる群から選択され；
Ｒ^１は、
ａ）ヘテロアリールオキシ、
ｂ）−Ｏ［（ＣＨ_２）_ｐＯ）］_ｍ−Ｒ^１２、
ｃ）次の式の基

からなる群から選択され、また
ｄ）Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６及びＲ^７の少なくとも１つがハロアルキルである場合、或いは、Ｒ^５及びＲ^６が、これらが結合している炭素と一緒にＣ_３〜Ｃ_８シクロアルキル、又はハロにより置換されたＣ_３〜Ｃ_８シクロアルキルを形成している場合、Ｒ^１はさらに、水素又は非置換若しくは置換Ｃ_１〜Ｃ_１２アルキルを表すことができ；
Ｒ^２は、水素、非置換又は置換Ｃ_１〜Ｃ_１２アルキル、非置換又は置換Ｃ_３〜Ｃ_８シクロアルキル、非置換又は置換アリール、非置換又は置換ヘテロアリール、ＯＲ^８、オキソ及びＮＲ^９ａＲ^９ｂからなる群から選択され；
Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６及びＲ^７は、それぞれ独立に、水素、ハロゲン、非置換又は置換Ｃ_１〜Ｃ_１２アルキル、非置換又は置換Ｃ_１〜Ｃ_１２ハロアルキル、非置換又は置換Ｃ_３〜Ｃ_８シクロアルキル、非置換又は置換アリール、非置換又は置換ヘテロアリール、ＯＲ^８、及びＮＲ^９ａＲ^９ｂからなる群から選択されるか、
或いは、Ｒ^５及びＲ^６は、これらが結合している炭素と一緒にＣ_３〜Ｃ_８シクロアルキル、又はハロにより置換されたＣ_３〜Ｃ_８シクロアルキルを形成しているか、
或いは、Ｒ^５及びＲ^６の一方は酸素原子を表し、この酸素原子がＣ_６に結合してそれぞれ６員又は５員の酸素含有複素環を形成しており；
Ｃ_９とＣ_１０との間の結合は単結合又は二重結合であってよく；
Ｒ^８、Ｒ^９ａ及びＲ^９ｂは、それぞれ独立に、水素、非置換又は置換Ｃ_１〜Ｃ_１２アルキル、非置換又は置換Ｃ_３〜Ｃ_８シクロアルキル、非置換又は置換アリール、非置換又は置換ヘテロアリール、グルコシルからなる群から選択されるか、或いは、Ｒ^９ａ及びＲ^９ｂは、これらが結合している窒素と一緒に、非置換若しくは置換複素環又は複素芳香族環（Ｏ、Ｎ及びＳから選択される１つ又は複数のさらなるヘテロ原子を場合によって含む）を形成していてもよく；
Ｒ^１０は、水素、非置換又は置換Ｃ_１〜Ｃ_１２アルキル、非置換又は置換Ｃ_３〜Ｃ_８シクロアルキル、非置換又は置換アリール、及び非置換又は置換ヘテロアリールからなる群から選択され；
Ｒ^１１及びＲ^１２は、それぞれ独立に、水素又はヒドロキシ保護基であり；
Ｒ^１３は、カルボキシ保護基であり；
Ｒ^１４は、天然又は非天然のアミノ酸残基であり；
ｎは、０、１及び２から選択され；
ｍは、１から２０の整数であり；また
ｐは、１から１２の整数である。 In one aspect, the compounds of the invention comprise jasmonate derivatives represented by the general structure of Formula I (salts, hydrates, solvates, polymorphs, optical isomers, geometric isomers, enantiomers, diastereomers, and Including these mixtures).

Where
A is
a) COR ¹ ,
b) O-COR ¹⁰ and c) OR ¹¹
Selected from the group consisting of;
R ¹ is
a) heteroaryloxy,
_{b) -O [(CH 2)} p O)] m -R 12,
c) group of formula

D) when at least one of R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is haloalkyl, or R ⁵ and R ⁶ are attached to the carbon to which they are attached together _C 3 -C ₈ cycloalkyl, or forming a _C 3 -C ₈ cycloalkyl substituted with halo, ^{R 1} is further represent a hydrogen or an unsubstituted or substituted _C 1 _{-C 12} alkyl Can do;
R ² is hydrogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, OR ⁸ , oxo and NR ^9a R Selected from the group consisting of ^9b ;
R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₁ -C ₁₂ haloalkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or is selected from the group consisting of oR ^8, and ^NR 9a ^{R 9b,}
Alternatively, R ⁵ and R ⁶ together with the carbon to which they are attached form a C ₃ -C ₈ cycloalkyl, or a C ₃ -C ₈ cycloalkyl substituted with halo,
Alternatively, one of R ⁵ and R ⁶ represents an oxygen atom, and this oxygen atom is bonded to C ₆ to form a 6-membered or 5-membered oxygen-containing heterocyclic ring, respectively;
The bond between C ₉ and C ₁₀ may be a single bond or a double bond;
R ⁸ , R ^9a and R ^9b are each independently hydrogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted hetero R ^9a and R ^9b are selected from the group consisting of aryl, glucosyl, or together with the nitrogen to which they are attached, unsubstituted or substituted heterocycles or heteroaromatic rings (from O, N and S) Optionally comprising one or more additional heteroatoms selected);
R ¹⁰ is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
R ¹¹ and R ¹² are each independently hydrogen or a hydroxy protecting group;
R ¹³ is a carboxy protecting group;
R ¹⁴ is a natural or non-natural amino acid residue;
n is selected from 0, 1 and 2;
m is an integer from 1 to 20; and p is an integer from 1 to 12.

In one currently preferred embodiment, the group A of formula I is COR ¹ . In one embodiment, R ¹ is heteroaryloxy, ie, a heteroaryl moiety described herein attached to oxygen. A presently preferred heteroaryloxy group is a quinolinyloxy group. In another embodiment, R ¹ is a polyoxyalkylene represented by the structure —O [(CH ₂ ) _p O] _m —R ¹² , wherein m and p are as described above for Formula I. is there. For example, the polyoxyalkylene group can be a polyoxy C ₁ -C ₁₂ alkylene (ie, when p is an integer from 1 to 12). A non-limiting example of a polyoxy C ₁ -C ₁₂ alkylene is polyethylene glycol represented by the structure, —O (CH ₂ —CH ₂ —O) _m —, where m is an integer from 1 to 20. A presently preferred value of m is 4. The group R ¹² represents hydrogen or a hydroxy protecting group. Any hydroxy protecting group described herein or known to those skilled in the art, for example, a silyl group (eg, trialkylsilyl, triarylsilyl, dialkylarylsilyl, diarylalkylsilyl, etc.), C _1- C ₄ alkyl, -CO- _(C 1 ~C _{6 alkyl), - SO 2 (C 1} ~C 6 _{alkyl), - SO 2 -Ar, -CO} -Ar (Ar is an aryl group as defined herein And —CO— (C ₁ -C ₆ alkyl) Ar (eg, a carboxybenzyl group) can be used. A currently preferred hydroxy protecting group for R ¹² is a silyl protecting group such as a trialkylsilyl protecting group (eg, t-butyldimethylsilyl).

In another embodiment, R ¹ is a group of the formula

The group R ¹³ can be any carboxy protecting group, for example alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 2-pentyl, 3 -Pentyl and the like. The group R ¹⁴ represents any natural or unnatural amino acid residue. Any natural and unnatural amino acid as defined herein and known to those skilled in the art can be incorporated into the jasmonate-amino acid derivatives of the present invention.

In another currently preferred embodiment, the group A of formula I is O-COR ¹⁰ where R ¹⁰ is unsubstituted or substituted C ₁ -C ₁₂ alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -Butyl, t-butyl, pentyl, 2-pentyl, 3-pentyl and the like. In yet another presently preferred embodiment, group A of formula I is OR ¹¹ and R ¹¹ is hydrogen or a hydroxy protecting group as defined above. A presently preferred hydroxy protecting group for R ¹¹ is a silyl protecting group such as a trialkylsilyl protecting group (eg, t-butyldimethylsilyl).

In one currently preferred embodiment, R ² of formula (I) is oxo (═O). In another currently preferred embodiment, R ² of formula (I) is OR ⁸ and R ⁸ is unsubstituted or substituted C ₁ -C ₁₂ alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- Butyl, t-butyl, pentyl, 2-pentyl, 3-pentyl and the like.

In one presently preferred embodiment, R ⁵ and R ⁶ together with the carbon to which they are attached (ie, C ₉ and C ₁₀ ) form an unsubstituted or substituted C ₃ -C ₈ cycloalkyl. Preferred substituents for the _C 3 -C ₈ cycloalkyl is _C 1 _{-C 12} alkyl or halogen. For example (for purposes of illustration and not limitation), R ⁵ and R ⁶ are taken together to form one (CRR ′) _a group (each of R and R ′ is independently hydrogen, C ₁ -C ₁₂ alkyl or halogen, a is set to a is) an integer from 1 to 6, may form a ring of 3 to 8-membered ring together with _{C 9} and _{C 10.} In one particular embodiment, R ⁵ and R ⁶ together represent one C (Hal) ₂ group (Hal is halogen), together with C ₉ and C ₁₀ , a halo-substituted cyclopropyl group Determine. Also, as will be apparent to those skilled in the art, any other substituent can likewise form a 3-8 membered cyclic structure with the carbon to which they are attached. For example, ^{R 3} and ^R 4; ^{R 3} and ^R 5; ^{R 3} and ^R 6; ^{R 3} and ^R 7; ^{R 4} and ^R 5; ^{R 4} and ^R 6; ^{R 4} and ^R 7; ^{R 5} and ^R 7; Any of these groups may form a cyclic structure in the same manner as described above together with the carbon to which they are bonded.

In one currently preferred embodiment, the bond between C ₉ and C ₁₀ is a double bond. In another currently preferred embodiment, the bond between C ₉ and C ₁₀ is a single bond. In another embodiment, each of R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ represents hydrogen. In yet another embodiment, the bond between C ₉ and C ₁₀ is a single bond and each of R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is hydrogen. In yet another embodiment, the bond between C ₉ and C ₁₀ is a double bond and each of R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is hydrogen.

In yet another embodiment, R ⁶ represents an oxygen atom bonded to C ₆ , thus forming an oxygen-containing 5-membered heterocycle. In yet another embodiment, R ⁵ represents an oxygen atom bonded to C ₆ , thus forming an oxygen-containing 6-membered heterocycle.

Specific examples of compounds of formula I include, but are not limited to:

本明細書において示されるように、前記化合物は、正常な細胞にはほとんど作用を及ぼさず、癌細胞に対して選択的細胞毒性を示す、非常に効力が高く選択的な細胞毒性作用剤であることが、予想外に見出された。このため、化合物１１は、米国特許第６４６９０６１号に開示されているジャスモネートグルコシル誘導体に比べて驚くほど上回る優れた性質を有する。 In yet another aspect, the present invention provides a jasmonate derivative represented by the structure of formula 11 (salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, and the like) A mixture of

As shown herein, the compound is a highly potent and selective cytotoxic agent that has little effect on normal cells and exhibits selective cytotoxicity against cancer cells. It was discovered unexpectedly. Thus, Compound 11 has surprisingly superior properties compared to the jasmonate glucosyl derivative disclosed in US Pat. No. 6,469,061.

Chemical Definitions As used herein, alone or as part of another group, the term “C ₁ to C ₁₂ alkyl” refers to linear and branched, saturated or unsaturated (eg, alkenyl, alkynyl). ) Group (unsaturated groups are only when the number of carbon atoms in the alkyl chain is 2 or more) and may include mixed structures. Preference is given to alkyl groups containing 1 to 4 carbon atoms (C ₁ to C ₄ alkyl). Examples of saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl, heptyl, Octyl, nonyl, decyl, undecyl, dodecyl and the like are included. Examples of alkenyl groups include vinyl, allyl, butenyl and the like. Examples of alkynyl groups include ethynyl, propynyl and the like. Similarly, the term “C ₁ to C ₁₂ alkylene” refers to a divalent group of 1 to 12 carbon atoms.

The C ₁ to C ₁₂ alkyl group may be unsubstituted or substituted by one or more substituents selected from the group consisting of: halogen, hydroxy, alkoxy, aryloxy, alkyl Aryloxy, heteroaryloxy, oxo, cycloalkyl, phenyl, heteroaryl, heterocyclyl, naphthyl, amino, alkylamino, arylamino, heteroarylamino, dialkylamino, diarylamino, alkylarylamino, alkylheteroarylamino, arylhetero Arylamino, acyl, acyloxy, nitro, carboxy, carbamoyl, carboxamide, cyano, sulfonyl, sulfonylamino, sulfinyl, sulfinylamino, thiol, C ₁ to C ₁₀ alkylthio, a Reelthio or a C ₁ to C ₁₀ alkylsulfonyl group. Any substituent may be unsubstituted or further substituted with any one of these substituents described above.

As used herein, the term “C ₃ to C ₈ cycloalkyl” used alone or as part of another group is saturated or unsaturated (eg, cycloalkenyl, cycloalkynyl), monocyclic or polycyclic Represents any group of Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of the cycloalkenyl group include cyclopentenyl, cyclohexenyl and the like. A cycloalkyl group can be unsubstituted or substituted with any one or more of the substituents defined above for alkyl. Similarly, the term “cycloalkylene” means a divalent cycloalkyl as defined above. In this case, the cycloalkyl group is attached at two positions connecting two separate additional groups.

  As used herein, the term “aryl” used alone or as part of another group refers to an aromatic ring system containing 6 to 14 ring carbon atoms. The aryl ring can be monocyclic, bicyclic, tricyclic and the like. Non-limiting examples of aryl groups include phenyl, naphthyl (including 1-naphthyl and 2-naphthyl) and the like. An aryl group can be unsubstituted or substituted with one or more of the groups defined above for alkyl through available carbon atoms.

  As used herein, the term “heteroaryl” used alone or as part of another group refers to a heteroaromatic system containing at least one heteroatom ring atom selected from nitrogen, sulfur and oxygen. To express. Heteroaryl contains 5 or more ring atoms. Heteroaryl groups can be monocyclic, bicyclic, tricyclic and the like. Also included in this expression are benzoheterocycles. Where the nitrogen is a ring atom, the present invention also contemplates nitrogen-containing heteroaryl N-oxides. Non-limiting examples of heteroaryl include thienyl, benzothienyl, 1-naphthothienyl, thiantenyl, furyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyrozyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, purinyl, quinolyl (eg 1-quinolinyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl and 8-quinolinyl), isoquinolinyl (eg 1-isoquinolinyl, 2-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl and 8-isoquinolinyl), naphthyridinyl (eg 1-naphthyridinyl, 2-naphthyridinyl), quinoxa Cycloalkenyl include quinazolinyl, cinnolinyl, pteridinyl, carbolinyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl and the like. A heteroaryl group may be optionally substituted through one or more groups as defined above for alkyl through available atoms. A heteroaryl group can be unsubstituted or substituted with one or more of the groups defined above for alkyl through available atoms.

  As used herein, the term “heterocycle” or “heterocyclyl” used alone or as part of another group refers to 1 to 4 heteroatoms (eg, oxygen, sulfur and / or nitrogen, especially Represents a 5- to 8-membered ring having nitrogen alone or together with a sulfur or oxygen ring atom. These 5- to 8-membered rings can be saturated, fully unsaturated or partially unsaturated, but rings that are fully saturated are preferred. Preferred heterocycles include piperidinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl, indolinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, dihydropyranyl , Tetrahydropyranyl and the like. A heterocyclyl group can be unsubstituted or substituted with one or more of the groups defined above for alkyl through available atoms.

  As used herein, the term “halogen” or “halo” used alone or as part of another group refers to chlorine, bromine, fluorine, and iodine.

As used herein, the term “amino” used alone or as part of another group refers to an NH ₂ group. As used herein, the terms “alkylamino, dialkylamino, arylamino, diarylamino, heteroarylamino, diheteroarylamino” and variations thereof refer to one or two substituents (the two substituents being the same For example, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl And amino substituted by thioalkyl and the like. These substituents may be further substituted with any one or more of the substituents defined above for alkyl. Furthermore, amino substituents (eg NR ^9a R ^9b ), together with the nitrogen atom to which they are attached, may form a heterocycle that may be any one of the heterocycles defined above. Good.

  The term “hydroxy” refers to an OH group. As used herein, the term “alkoxy”, “aryloxy”, “arylalkyloxy” or “heteroaryloxy” used alone or as part of another group refers to any of the above, attached to an oxygen atom. Including alkyl, aryl or heteroaryl groups. Non-limiting examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and similar groups. An example of an aryloxy group is phenyloxy (phenoxy). An alkoxy, aryloxy, arylalkyloxy or heteroaryloxy group can be unsubstituted or substituted with any one or more of the substituents defined above for alkyl.

As used herein, the term “hydroxy protecting group” refers to an easily cleavable group attached to a hydroxy group. The nature of the hydroxy protecting group is not critical as long as the derivatized hydroxyl group is stable. An example of a hydroxy protecting group is a silyl group, which can be substituted with alkyl (trialkylsilyl), aryl (triarylsilyl), or combinations thereof (eg, dialkylphenylsilyl). Preferred examples of silyl protecting groups are trimethylsilyl (TMS) or di-t-butyldimethylsilyl (TBDMS). Other examples of hydroxy protecting groups, _e.g., C 1 -C ₄ alkyl, -CO- _(C 1 ~C _{6 alkyl), - SO 2 - (C} 1 ~C 6 alkyl), - SO ₂ - aryl, -CO-Ar (Ar is an aryl group as defined above), and -CO- _(C 1 ~C ₆ alkyl) Ar (e.g., carboxymethyl benzyl group) include. Other examples of hydroxy protecting groups are C.I. B. Reese and E.E. Haslam "Protective Groups in Organic Chemistry" G. W. McOmie, Plenum Press, New York, New York, 1973, chapters 3 and 4, respectively, W. Greene and P.M. G. M.M. Wuts “Protective Groups in Organic Synthesis”, 2nd edition, John Wiley and Sons, New York, NY, 1991, Chapters 2 and 3, each of which is incorporated herein by reference.

  As used herein, the term “carboxy” used alone or as part of another group refers to a COO group and further includes carboxylates of the formula COOM, where M is a metal ion. The term “metal ion” refers to alkali metal ions such as sodium, potassium or lithium, and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.

As used herein, the term “carboxy protecting group” refers to one of the derivatives of a carboxylic acid group that is widely used to block or protect a carboxylic acid group. Non-limiting examples of carboxy protecting groups are C ₁ -C ₁₂ alkyl group, this group, together with carboxyl group, an ester (e.g., methyl ester) defining a. Another example of a carboxy protecting group is a benzyl group. Other examples of these groups are described in E.I. Haslam "Protective Groups in Organic Chemistry" G. W. McOmie, Plenum Press, New York, New York, Chapter 1973, Chapter 5; W. Greene and P.M. G. M.M. Wuts “Protective Groups in Organic Synthesis”, 2nd edition, John Wiley and Sons, New York, NY, 1991, chapter 1991, each of which is incorporated herein by reference.

  The term “acyl” includes groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, benzoyl and the like. Preferred acyl groups are acetyl and benzoyl.

  As used herein, the term “thio” used alone or as part of another group refers to an SH group. As used herein, the term “alkylthio”, “arylthio” or “arylalkylthio” used alone or as part of another group refers to any of the above alkyl, arylalkyl or aryl groups attached to a sulfur atom. Represents.

As used herein, the term “sulfonyl” used alone or as part of another group refers to —S (O) ₂ —. As used herein, the term “sulfonylamino” used alone or as part of another group refers to —S (O) ₂ —NH. The term “sulfinyl” represents —S (O) —. As used herein, the term “sulfinylamino” used alone or as part of another group refers to —S (O) —NH. As used herein, the term “oxo” used alone or as part of another group refers to —O—. As used herein, the term “cyano” used alone or as part of another group refers to a CN group. As used herein, the term “nitro” used alone or as part of another group refers to a NO ₂ group.

As used herein, the term “polyoxyalkylene” used alone or as part of another group, eg, “polyoxyC ₁ -C ₁₂ alkylene”, is defined as oxyalkylene (eg, bonded to oxygen, as defined above). has been _C 1 _{-C 12} 2 or more units of alkylene moiety), for example, the structure _{-O [(CH 2) p O} ] m - (m is an integer of 1 to 20, p is from 1 to 12 integer Represents a compound represented by: An example of a polyoxy C ₁ -C ₁₂ alkylene group is the polyethylene glycol represented by the structure —O (CH ₂ —CH ₂ —O) _m —, eg, —O (CH ₂ —CH ₂ —O) ₄ —.

Similarly, as used herein, the term “polyaminoalkylene”, eg, “polyaminoC ₁ -C ₁₂ alkylene”, used alone or as part of another group, refers to aminoalkylene (eg, bonded to NH, above in defined _C 1 _{-C 12} 2 or more units of alkylene moiety), for example, the structure _{-NH [(CH 2) p NH} ] m - (m is an integer of 1 to 20, p is from 1 12 Which is an integer of An example of a polyamino C ₁ -C ₁₂ alkylene group is polyethylene diamine represented by the structure —NH (CH ₂ —CH ₂ —NH) _m .

Similarly, as used herein, the term “polythioalkylene” used alone or as part of another group, eg, “polythioC ₁ -C ₁₂ alkylene” refers to thioalkylene (eg, bonded to sulfur, Two or more units of the above defined C ₁ -C ₁₂ alkylene moiety), for example, the structure —S [(CH ₂ ) _p S] _m —, where m is an integer from 1 to 20 and p is from 1 Is an integer of 12). An example of a polythio C ₁ -C ₁₂ alkylene group is represented by the structure —S (CH ₂ —CH ₂ —S) _m .

  The term “natural and non-natural amino acids” (α-amino acids) includes both naturally occurring amino acids and other non-natural amino acids, including both optically active (D and L) isomers and even racemic derivatives. Represent. As envisioned herein, an amino acid is attached to a jasmonate derivative by forming an amide bond between the carboxyl group of the jasmonate and the amino group of the amino acid. Naturally occurring amino acids are glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, γ-carboxyglutamic acid, arginine Ornithine and lysine. Examples of non-natural α-amino acids include N-methylalanine, α-aminoisobutyric acid, α-aminobutyric acid, γ-aminobutyric acid, citrulline, N-methyl-glycine, N-methyl-glutamic acid, homocitrulline, homoproline, Homoserine, hydroxyproline, norleucine, 4-aminophenylalanine, statin, hydroxylysine, kynurenine, 3- (2′-naphthyl) alanine, 3- (1′-naphthyl) alanine, methionine sulfone, (t-butyl) alanine, ( t-butyl) glycine, 4-hydroxyphenylglycine, aminoalanine, phenylglycine, vinylalanine, propargyl-glycine, 1,2,4-triazole-3-alanine, thyronine, 6-hydroxytryptophan, 5-hydroxytryptophan, 3 -Hydroxy Nurenin, 3-aminotyrosine, trifluoromethyl-alanine, 2-thienylalanine, (2- (4-pyridyl) ethyl) cysteine, 3,4-dimethoxy-phenylalanine, 3- (2′-thiazolyl) alanine, ibotenic acid 1-amino-1-cyclopentane-carboxylic acid, 1-amino-1-cyclohexanecarboxylic acid, kisscaric acid, 3- (trifluoromethylphenyl) alanine, (cyclohexyl) glycine, thiohistidine, 3-methoxytyrosine, elast Tachinal, norleucine, norvaline, alloisoleucine, homoarginine, thioproline, dehydroproline, hydroxyproline, homoproline, α-amino-n-butyric acid, cyclohexylalanine, 2-amino-3-phenylbutyric acid, β-2- and 3- Thienylalani , Β-2- and 3-furanylalanine, β-2-, 3- and 4-pyridylalanine, β- (benzothienyl-2- and 3-yl) alanine, β- (1- and 2-naphthyl) O-alkylated derivatives of serine, threonine or tyrosine; S-alkylated cysteine, S-alkylated homocysteine; O-sulfate, O-phosphate and O-carboxylate of tyrosine; 3- (sulfo ) Tyrosine, 3- (carboxy) tyrosine, 3- (phosphotyrosine), 4-methanesulfonic acid ester of tyrosine, 4-methanephosphonic acid ester of tyrosine, 3,5-diiodotyrosine, 3-nitrotyrosine, ε-alkyl Lysine, as well as δ-alkylornithine are included.

  All stereoisomers of the compounds of the present invention are envisioned as either a mixture or in pure or substantially pure form. The compounds of the present invention may have asymmetric centers at any of the atoms. For this reason, these compounds may exist in the form of enantiomers or diastereomers or as mixtures thereof. The present invention relates to any racemate (ie, a mixture containing equal amounts of each enantiomer), one enantiomerically enriched mixture (ie, one enantiomerically enriched mixture), pure enantiomer, or The use of diastereomers or mixtures thereof is envisaged. A chiral center can be designated as R or S or R, S, or d, D, 1, L, or d, 1, D, L. Compounds containing amino acid residues include residues of D-amino acids, L-amino acids, or racemic derivatives of amino acids. Compounds containing sugar residues include residues of D-sugars, L-sugars, or racemic derivatives of sugars. In addition, some of the compounds of the present invention contain one or more double bonds. The present invention is meant to encompass all structural and geometric isomers, including cis, trans, E and Z isomers.

  One or more compounds of the invention may exist as a salt. The term “salt” includes both base and acid addition salts, including but not limited to carboxylates or salts with amino nitrogens, and by the organic and inorganic anions and cations described below. Contains the salt produced. In addition, the term includes salts formed by standard acid-base reactions with basic groups (eg, amino groups) and organic or inorganic acids. Such acids include hydrochloric acid, hydrofluoric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, acetic acid, succinic acid, citric acid, lactic acid, maleic acid, fumaric acid, palmitic acid, cholic acid, pamoic acid, mucoic acid , D-glutamic acid, D-camphoric acid, glutaric acid, phthalic acid, tartaric acid, lauric acid, stearic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, sorbic acid, picric acid, benzoic acid, cinnamic acid, and the like Contains acid.

  The term “organic or inorganic cation” refers to the counter ion for the carboxylate anion of the carboxylate. These counterions include alkali and alkaline earth metals (eg, lithium, sodium, potassium, barium, aluminum and calcium); ammonium and mono-, di- and tri-alkylamines such as trimethylamine, cyclohexylamine; and Organic cations such as dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis (2-hydroxyethyl) ammonium, phenylethylbenzylammonium, dibenzylethylenediammonium, and similar cations are selected. See, for example, “Pharmaceutical Salts” (Berge et al., J. Pharm. Sci., 66: 1-19 (1977)), which is incorporated herein by reference. Other cations encompassed by the above terms include protons of procaine, quinine and N-methylglucosamine, and protons of basic amino acids (eg, glycine, ornithine, histidine, phenylglycine, lysine and arginine). Additional types are included. Furthermore, zwitterionic forms of the compounds of the invention formed by carboxylic acids and amino groups are also envisaged.

  The present invention also includes solvates of the compounds of the invention and their salts. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, solvates can be isolated. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanol adducts, methanol adducts and the like. “Hydrate” is a solvate wherein the solvent molecule is water.

  The present invention also includes polymorphs of the compounds of the present invention and salts thereof. The term “polymorph” refers to a specific crystalline state of a substance, which can be characterized by specific physical properties such as X-ray diffraction, IR spectrum, melting point, and the like.

Use in Therapy As described herein, the compounds of the present invention are potent cytotoxic agents that can inhibit the growth of cancer cells in a variety of cancer cells. Thus, the present invention provides a powerful method for the chemoprevention and treatment of cancer not previously described.

  That is, in one aspect, the present invention provides a method for inhibiting the growth of cancer cells comprising contacting the cancer cells with a therapeutically effective amount of a compound of the present invention as described herein. Provide further. Preferably, the compound is one or more of the compounds represented by any of formulas I, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 as described herein. is there. In some embodiments, the compound is administered in a pharmaceutical composition.

  Furthermore, the present invention provides a method for treating cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of the present invention as described herein. Preferably, the compound is one or more of the compounds represented by any of formulas I, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 as described herein. is there. In some embodiments, the compound is administered as a pharmaceutical composition. In one aspect, the subject is a mammal, preferably a human. However, the present invention also contemplates the use of the compounds of the present invention against non-human mammals, for example in veterinary medicine.

  Furthermore, the present invention relates to compounds of any of formulas I, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 according to the present invention in the preparation of therapeutic agents useful for the treatment of cancer. About the use of.

  In the description and claims of the present application, when "treatment or suppression of malignant cell proliferative disease or disorder", "treatment or suppression of non-solid cancer", or "treatment or suppression of tumor" is used It should always be understood that they are assumed to include tumorigenesis, primary tumor, tumor progression or tumor metastasis.

  The term “inhibition of growth” for cancer cells is in the context of the present invention due to cell death relative to the control (cell death, which can be necrosis, apoptosis or some other type of cell death, or a combination thereof). ); Decrease in cell growth rate, ie, the total number of cells may increase, but increase at a lower or lower rate than the increase in the control; even if the total number of cells does not change compared to the control, Reduction in cell invasiveness (eg, as determined by soft agar assay); progression from less differentiated cell type to more differentiated cell type; slowing malignant transformation; or alternatively, from one stage to the next This represents a decrease in at least one of the slowing of cancer cell progression to:

  In the context of the present invention, the term “cancer treatment” refers to a decrease in the growth rate of a cancer (ie, the cancer still grows but grows at a slower rate); In at least one of the following: Stasiness of growth: in preferred cases, the tumor shrinks or decreases in size. The term also includes a reduction in the number of metastases, a reduction in the number of new metastases that are generated, a slowing of cancer progression from one stage to another, and a reduction in angiogenesis induced by cancer. . In the most preferred case, all tumors disappear. Further included in this term are prolongation of the survival of the subject undergoing treatment, slowing of disease progression, tumor regression, and the like. The term also encompasses prevention in prophylactic situations or against individuals susceptible to tumors. Administration of the compounds of the present invention reduces the likelihood that an individual will suffer from the disease. In a preferred situation, an individual to whom a compound of the invention is administered does not suffer from the disease.

  As used herein, the term “administering” refers to contacting a compound of the present invention. Administration can be performed on a cell or tissue culture, or a living organism (eg, a human). In one aspect, the invention includes administering a compound of the invention to a subject that is human.

  A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of a medical condition with the purpose of reducing or eliminating these signs. A “therapeutically effective amount” of a compound of the invention is an amount of the compound sufficient to produce a beneficial effect in the subject to which the compound is administered.

  In the context of the present invention, the term “cancer” includes all types of tumors, whether in the form of solid or non-solid tumors, both malignant and pre-malignant conditions, as well as their metastases. including.

  Cancers can be classified in two ways, depending on the type of tissue in which the cancer occurs (tissue type) and the primary site, ie, the body location where the cancer first developed. The international standard for histology classification and nomenclature is International Classification of Diseases for Oncology, Third Edition.

  From a histological point of view, there are hundreds of different cancers, which are classified into five main types: carcinoma, sarcoma, myeloma, leukemia, and lymphoma. In addition, there are also some mixed types of cancer.

  A carcinoma is an epithelial-derived malignant tumor or cancer of the body's internal or external lining. Carcinomas, malignant tumors of epithelial tissue account for 80 to 90 percent of all cancer cases. Epithelial tissue is found throughout the body. It is present in the skin and also in the covering and lining of organs and internal passages (eg the gastrointestinal tract).

  Carcinomas are divided into two main subtypes: adenocarcinoma (which is expressed in the organ or gland) and squamous cell carcinoma (which occurs in the squamous epithelium). Many carcinomas affect secretable organs or glands (eg, breast producing milk, or lungs that secrete mucus), or the large intestine or prostate or bladder.

  Adenomas usually start in the mucosa and are initially observed as thickened plaque-like white mucosa. They often spread easily to the soft tissue where they occur. Squamous cell carcinoma occurs in many parts of the body.

  Sarcoma refers to cancer that occurs in supporting and connective tissues such as bone, tendons, cartilage, muscle, and adipose tissue. Usually occurring in young adults, the most common sarcoma often manifests as a painful mass on the bone. Sarcomas usually resemble the tissue in which they grow.

  Examples of sarcomas are osteosarcoma, or osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelioma or mesothelioma (Membrane lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma or vascular endothelial sarcoma (blood vessel); liposarcoma (adipose tissue); glioma or astrocytoma (neurogenic connective tissue found in the brain) Myxosarcoma (primitive embryonic connective tissue); mesenchymal or mesodermal mixed tumor (mixed connective tissue type);

  Myeloma is a cancer that arises in the plasma cells of the bone marrow. Plasma cells produce some of the proteins found in the blood.

  Leukemia ("non-solid tumor" or "blood cancer") is a cancer of the bone marrow (blood cell production site). The disease is often accompanied by overproduction of immature leukocytes. Leukemia can also affect red blood cells, resulting in poor blood clotting and fatigue due to anemia. Examples of leukemia include the following: myeloid or granulocytic leukemia (malignant tumors of the bone marrow and granulocyte series); lymphoid, or lymphocytic, or lymphoblastic leukemia (lymphoid and lymphoid) Blood cell lineage malignancy); polycythemia vera or red blood disease (malignant tumors of various blood cell products but mainly erythrocyte malignancies).

  Lymphomas develop in glands or nodes of the lymphatic system (white blood cells that purify fluid and fight infection, or a network of ducts, nodes, and organs that produce lymphocytes, particularly the spleen, tonsils, and thymus). Unlike leukemia, which is sometimes called a non-solid tumor, “lymphoma” is a “solid cancer”. Lymphoma can also occur in certain organs such as the stomach, chest or brain. These lymphomas are called extranodal lymphomas. Lymphomas are subclassified into two categories: Hodgkin lymphoma and non-Hodgkin lymphoma. The presence of Reed-Sternberg cells in Hodgkin lymphoma diagnostically distinguishes Hodgkin lymphoma from non-Hodgkin lymphoma.

  A mixed type of cancer includes several types of cells. The plurality of type elements can be within one category or from different categories. Some examples are: adenosquamous carcinoma; mesoderm mixed tumor; carcinosarcoma; teratocarcinoma;

  As used herein, the term “cancer” includes the above classes of carcinoma, sarcoma, myeloma, leukemia, lymphoma and mixed type tumors. In particular, the term cancer refers to lymphoproliferative disease, breast cancer, ovarian cancer, prostate cancer, cervical cancer, endometrial cancer, bone cancer, liver cancer, stomach cancer, colon cancer, pancreatic cancer, thyroid cancer, head and neck cancer, central It includes cancer of the nervous system, cancer of the peripheral nervous system, skin cancer, kidney cancer, and all these metastases. More specifically, as used herein, this term refers to hepatocellular carcinoma, hematoma, hepatoblastoma, rhabdomyosarcoma, esophageal cancer, thyroid cancer, ganglioblastoma, fibrosarcoma, myxosarcoma, liposarcoma, cartilage Sarcoma, osteogenic sarcoma, chordoma, hemangiosarcoma, endothelial sarcoma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, melanoma, squamous cell carcinoma, basal cell carcinoma, gland Cancer (highly differentiated, moderately differentiated, poorly differentiated or undifferentiated), renal cell carcinoma, adrenoma, adrenal-like adenocarcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, fetal cancer, Wilms tumor, testicular tumor, lung cancer (small) Cell, non-small cell and large cell lung cancer), bladder cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, retinoblastoma, neuroblastoma, Colorectal cancer, rectal cancer, hematopoietic malignancy (acute myeloid leukemia, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, Sex lymphocytic leukemia, mast cell leukemia, multiple myeloma, spinal lymphoma, Hodgkin's lymphoma, including non-Hodgkin's lymphoma, representing the will) include all types of leukemias and lymphomas.

  More preferably, the cancer is prostate cancer, breast cancer, skin cancer, colon cancer, lung cancer, pancreatic cancer, lymphoma, myeloma, leukemia, head and neck cancer, kidney cancer, stomach cancer, ovarian cancer, bone cancer, liver cancer, or thyroid gland Selected from the group consisting of cancer. Even more preferably, the cancer is selected from leukemia (including lymphoblastic leukemia), lung cancer, melanoma, kidney cancer, stomach cancer and colon cancer.

  In other embodiments of the use in the preparation of a therapeutic agent, the therapeutic agent further comprises at least one active chemotherapeutic agent other than the compound of the present invention. In certain embodiments, the compounds of the invention can be administered with at least one conventional chemotherapeutic agent that is effective in the treatment of certain cancers. Administration can be simultaneous (together in one dosage form or as separate dosage forms) or sequential. When administered sequentially, the jasmonate derivative may be administered before or after treatment with the additional chemotherapeutic agent. The combination of a compound of the present invention and a conventional drug allows the drug to be administered at a low dosage, so that the subject experiences significantly fewer side effects, yet at the same time, the full effect of chemotherapy is achieved. Is done.

Pharmaceutical Compositions Although the heterocyclic jasmonate derivatives of the present invention can be administered alone, these compounds can be administered as a pharmaceutical composition comprising the jasmonate derivative together with a pharmaceutically acceptable carrier or excipient. Assumed.

  Preferably, in the pharmaceutical composition the active ingredient is dissolved in any acceptable lipid carrier (eg micelles or liposomes formed, eg fatty acids, oils). Further in accordance with a preferred embodiment of the present invention the composition further comprises at least one other chemotherapeutic agent.

  The pharmaceutical composition of the present invention can be applied by various routes including oral, rectal, transdermal, parenteral (subcutaneous, intraperitoneal, intravenous, intraarterial, transdermal and intramuscular), topical, intranasal, or suppository. Can be formulated to be administered. Such compositions are prepared in a manner well known in the pharmaceutical art and as active ingredients at least one of the compounds of the invention described herein above and a pharmaceutically acceptable excipient. Agent or carrier. The term “pharmaceutically acceptable” is approved by a federal or state government regulatory agency for use in animals, and more particularly in humans, or is a U.S. Pharmacopoeia or other commonly recognized pharmacy. Means that it is listed in

  During the preparation of a pharmaceutical composition according to the present invention, the active ingredient is usually mixed with a carrier or excipient that can be a solid, semi-solid, or liquid substance. Compositions are tablets, pills, capsules, pellets, granules, powders, lozenges, sachets, cachets, elixirs, suspensions, dispersions, emulsions, solutions, sprays, aerosols It can be in the form of an ointment, soft and hard gelatin capsule, suppository, sterile infusion solution, and sterile packaged powder (for example up to 10% by weight of active compound) (as a solid or in a liquid medium).

  The carrier may be any of those commonly used and is limited only by chemical-physical considerations (eg, lack of solubility and reactivity with the compounds of the present invention) and route of administration. The choice of carrier will be determined by the particular method used to administer the pharmaceutical composition. Some examples of suitable carriers include lactose, glucose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water And methylcellulose. The formulations further include lubricants such as talc, magnesium stearate, and mineral oils; wetting agents, surfactants, emulsifiers and suspending agents; preservatives such as methyl- and propylhydroxybenzoates; sweeteners Flavoring agents, coloring agents, buffering agents (eg acetate, citrate or phosphate), disintegrants, moistening agents, antibacterial agents, antioxidants (eg ascorbic acid or bisulfite) Sodium), chelating agents (eg, ethylenediaminetetraacetic acid), and tonicity modifiers, such as sodium chloride. Other pharmaceutical carriers are sterile liquids such as water and oils (including oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.), polyethylene glycol, glycerin, propylene It can be a glycol or other synthetic solvent. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.

  In preparing solid compositions such as tablets, the active principle is mixed with pharmaceutical excipients so as to produce a solid pre-blended composition comprising a homogeneous mixture of the compounds of the invention. When these pre-blended compositions are homogeneous, the active ingredients are evenly dispersed throughout the composition, so that equally effective units of the composition, such as tablets, pills and capsules It means that it can be easily subdivided into dosage forms. In this case, the solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, 0.1 to about 500 mg of the active ingredient of the present invention.

  Any method may be used to prepare the pharmaceutical composition. Solid dosage forms can be prepared by wet granulation, dry granulation, direct compression, and the like.

  The solid dosage forms of the present invention may be coated or otherwise configured so as to obtain a dosage form that provides benefits from sustained action. For example, a tablet or pill can comprise an internal dosage component and an external dosage component, the latter being in the form of the former envelope. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allows the internal component to pass intact into the duodenum or to delay the release of the internal component. To do. Various materials can be used for such enteric layers or coatings, such materials include many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate. Is included.

  For oral administration or administration by injection, liquid forms in which the compositions of the invention may be incorporated include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and edible Flavored emulsions with oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles are included.

  Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered by the oral or nasal respiratory route for local or systemic effect. The composition, preferably in a pharmaceutically acceptable solvent, can be nebulized by use of an inert gas. The atomized solution may be drawn directly from the atomizing device, or the atomizing device may be attached to a face mask stent or intermittent positive pressure breathing machine. . Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

  Another formulation used in the methods of the present invention uses transdermal delivery devices (“patches”). Such transdermal patches can be used to continuously or discontinuously infuse a compound of the present invention in controlled amounts. The construction and use of transdermal patches for drug delivery is well known in the art.

  In yet another aspect, the compositions of the present invention are prepared for topical administration, eg, as an ointment, gel, drop or cream. For topical administration to the body surface using, for example, creams, gels, drops, ointments and the like, the compounds of the invention are prepared and attached to physiologically acceptable diluents with or without pharmaceutical carriers. The present invention may be used topically or transdermally to treat cancer, such as melanoma. Adjuvants for topical or gel-based forms may include, for example, sodium carboxymethylcellulose, polyacrylates, polyoxyethylene-polyoxypropylene-block polymers, polyethylene glycols and wood wax alcohol.

  Alternative formulations include nasal sprays, liposome formulations, sustained release formulations, controlled release formulations, etc., as is known in the art.

  The composition of the present invention is preferably formulated as a dosage unit form. The term “dosage unit form” refers to a physically separate unit suitable as a unitary dosage for human patients and other animals, each unit producing a desired therapeutic effect. A calculated predetermined amount of the active substance is included together with a suitable pharmaceutical excipient.

  In preparing a formulation, the active ingredient may need to be milled to the proper particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it is usually milled to a particle size of less than 200 mesh. If the active ingredient is substantially water soluble, the particle size is usually adjusted by milling, for example to about 40 mesh, so as to obtain a substantially uniform distribution in the formulation.

  It may be desirable to administer the pharmaceutical composition of the invention locally to the part in need of treatment. This includes, but is not limited to, for example, local continuous infusion during surgery, by topical application (eg in connection with post-surgical wound dressing), by infusion, by catheter, by suppository, or by implant (this implant is Porous, non-porous, or jelly-like substance). In some preferred embodiments, administration can be by direct injection (eg, by an injector) at the site of the tumor or neoplastic or preneoplastic tissue.

  The compounds of the invention may also be administered by any convenient route, for example by continuous or bolus injection, by absorption through epithelial linings (eg oral mucosa, rectal and intestinal mucosa, etc.). It may also be administered with other therapeutically active agents. Although administration is preferably local, it may be systemic. Further, the pharmaceutical composition of the present invention can be applied in any suitable manner, including intracerebroventricular and intrathecal injection (intraventricular infusion can be facilitated, for example, by an intraventricular catheter attached to a container). It may be desirable to introduce it into the central nervous system by any route. Pulmonary administration can also be used, for example, by use of a formulation comprising an inhaler or nebulizer, and an aerosolizing agent.

  The compounds of the present invention can be delivered as immediate or controlled release systems. In one embodiment, continuous infusion pumps (eg, those used to deliver chemotherapeutic agents to specific organs or tumors) can be used to administer compounds of the present invention (Buchwald et al., 1980, Surgery 88: 507; Saudek et al., 1989, N. Engl. J. Med. 321: 574). In a preferred form, the compounds of the present invention are administered in combination with a biodegradable, biocompatible polymer implant that releases the compounds of the present invention at a selected site over a controlled period of time. Examples of preferred polymeric materials include polyanhydrides, polyorthoesters, polyglycolic acid, polylactic acid, polyethylene vinyl acetate, copolymers and blends thereof ("Medical applications of controlled release" (1974, edited by Langer and Wise). CRC Pres., Boca Raton, FL) In yet another embodiment, the controlled release system requires only a fraction of the systemic dose because it can be placed in the vicinity of the therapeutic target.

  In addition, sometimes the pharmaceutical compositions of the present invention may be formulated for parenteral administration (subcutaneous, intravenous, intraarterial, transdermal, intraperitoneal or intramuscular injection). Aqueous and non-aqueous isotonic sterile infusion solutions (which may include antioxidants, buffers, bacteriostats, and solutes that make the intended recipient's blood and formulation isotonic), and aqueous And non-aqueous sterile suspensions including suspensions, solubilizers, thickeners, stabilizers, and preservatives. Oils such as petroleum oils, animal oils, vegetable oils, or synthetic oils, soaps such as fatty alkali metal salts, ammonium salts, and triethanolamine salts, and suitable detergents may also be used for parenteral administration. The formulation can also be used for direct intratumoral injection. In addition, the composition can include one or more nonionic surfactants to minimize or eliminate irritation at the site of injection. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and ethylene oxide high molecular weight adducts comprising a hydrophobic base formed by condensation of propylene oxide and propylene glycol.

  Parenteral formulations can be provided as single-dose or multiple-dose sealed containers, such as ampoules and vials, and require only the addition of a sterile liquid carrier (eg, water) for injection immediately prior to use. Can be stored in a lyophilized state. Injection solutions and suspensions formulated as needed are known in the art and can be prepared from sterile powders, granules and tablets of the kind previously described.

  Alternatively, the jasmonate derivatives of the present invention can be used for hemodialysis, such as leukophoresis and other related methods, for example, blood can be used in various ways such as dialysis through columns / hollow fiber membranes, cartridges, etc. The method is removed from the patient, treated ex-vivo with the jasmonate derivative and returned to the patient after treatment. Such treatment methods are well known and described in the art. For example, Kolho et al. (J. Med. Virol. 1993, 40 (4): 318-21); Ting et al. , (Transplantation, 1978, 25 (1): 31-3); the contents of which are hereby incorporated by reference in their entirety.

  The amount of a compound of the invention that is effective in the treatment of a particular disorder or condition, including cancer, depends on the nature of the disorder or condition and can be determined by standard clinical techniques. In addition, in vitro assays may optionally be employed to help establish optimal dosage ranges. The exact dose used in the formulation will also depend on the route of administration and the severity of the disease or disorder and should be determined according to the judgment of the physician and the circumstances of each patient. Preferred dosages will be in the range of 0.01-1000 mg / kg body weight, more preferably 0.1 mg / kg to 100 mg / kg, even more preferably 1 mg / kg to 10 mg / kg. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test bioassays or systems.

  The following examples are set forth in order to more fully illustrate certain embodiments of the invention. However, they should in no way be construed as limiting the broad scope of the invention. Those skilled in the art can easily create many variations and modifications of the principles disclosed herein without departing from the scope of the invention.

(Example 1)
Cytotoxicity of jasmonate derivatives against leukemia cells New jasmonate derivatives (compounds 1-11) were tested for cytotoxicity in three cancer cell lines.
A) Molt-4-human acute lymphoblastic leukemia cell line B) CT26-murine colon cancer cell line C) MCF7-human breast cancer cell line

  New derivatives were also tested on normal lymphocytes (PBL) obtained from healthy donors and stimulated by plant agglutinin (PHA) and TPA. The experimental set-up as well as the IC50 values obtained for various cell lines are listed below.

Experimental setup Mononuclear cells were separated from peripheral blood of healthy donors by Ficoll-Hypaque density gradient centrifugation. Mononuclear cells were attached to plastic dishes to remove macrophages. Cell density was as follows. Non-adherent peripheral blood lymphocytes (PBL) were preincubated with 0.8 μg / mL PHA and 5 ng / mL TPA for 24 hours and then used for further experiments.

The cell density was as follows: Molt-4 (2.5 × 10 ⁴ cells in 100 μL per well) seeded in a 96-well plate, CT26 (5 × 10 ³ cells in 100 μL per well) ), MCF7 (5 × 10 ³ cells in 100 μL per well) and PBL (1.5 × 10 ⁵ cells in 100 μL per well). Adherent cells (CT26 and MCF7) were allowed to adhere overnight.

  The jasmonate derivative was added for 24 hours at concentrations ranging from 0.005 to 0.5 mM. Each experimental point was carried out in triplicate. Untreated cells were used as a control. The jasmonate derivative was prepared as a 167 mM stock solution in 100% ethanol. Dilution was performed with culture medium and ethanol so that the final concentration of ethanol in each well was 0.6%. This ethanol concentration by itself did not affect the viability of any cell line.

  Optical density representing viable cells was determined using the XTT Cell Proliferation Kit assay (Biological industries, Beit-Haemek, Israel).

  The percentage of optical density is directly proportional to the number of living cells in the culture. Cytotoxicity (%) was calculated as follows: [(OD of control cells−OD of drug treated cells) / OD of control cells] × 100.

Results IC50 values for various compounds in various cell lines are listed in Table 1 below.

(Example 2)
Selectivity of jasmonate derivatives: Compound 9 and Compound 11
Experimental setup Mononuclear cells were isolated from peripheral blood of healthy donors and processed as described above. Non-adherent PBLs were preincubated without the above PHA and TPA. Molt-4 and PBL cells were seeded in 96-well plates as described above.

  The jasmonate derivative compounds 9 and 11 were added at concentrations ranging from 0.005 to 0.5 mM for 24 hours. Each experimental point was carried out in triplicate. Untreated cells were used as a control. The jasmonate derivative was prepared as a 167 mM stock solution in 100% ethanol and dilution with substrate was performed as described above. The optical density and the percentage of cytotoxicity were determined as described above.

  As shown in FIGS. 1A and 1B, there is sufficient therapeutic tolerance that compounds 9 and 11 can kill leukemia cells without substantially affecting normal lymphocytes. These results indicate that the compounds of the present invention have the ability to exert selective cytotoxic effects on cancer cells and do not substantially act on normal cells.

(Example 3)
Effect of Compound 9 tested in vitro in chronogenic assay (TCA) on tumors from various patients Experimental setup Cancer cells were taken directly from cancer patients using a tumor-colony assay : athymic agenesis Human solid tumor xenografts grown subcutaneously at the passage of nude mice were removed and dissociated to obtain isolated tumor cells. Viable cells were added to the culture medium supplemented with agar and plated in 24-multiwell dishes. Test compounds were added to the cultures, the cultures were incubated at 37 ° C. for 6-20 days and colony growth was monitored using an inverted microscope. When the maximum number of colonies were formed, the colonies were counted and stained with a vital dye 24 hours before evaluation. The effect of the drug was expressed by the percentage of colony formation obtained by comparing the average colony count of treated wells with the average colony count of untreated controls. The IC50 value (the drug concentration required to inhibit colony formation by 50%) is the compound concentration vs. It was determined by plotting the relative colony count. The results are shown in Table 2.

  Comparing these values with the cell line results (Table 1), it is clear that compound 9 is more potent against patient-derived tumors than against cell lines.

(Example 4)
The ability of Compound 9 to induce a decrease in ATP levels in CT26 colon cancer cells The ability of Compound 9 to induce a decrease in ATP levels in CT26 colon cancer cells was evaluated. It was previously found that methyl jasmonate, a natural jasmonate, can cause a decrease in ATP levels in cancer cells (Fingrut et al., 2005, Fingrut O, et al. Br. J. Pharmacol. 146: 800-808, 2005). However, since dead cells will not contain ATP, these experiments were performed under conditions where no cytotoxic effects were evident (dose and exposure time). The purpose of this experiment was to evaluate whether a decline in ATP precedes death.

Experimental setup CT26 cells were exposed to Compound 9 for 3 hours and ATP levels were measured using CellTiter-Glot Luminescent Cell Viability Assay (Promega, Madison, Wis., USA). As can be seen in FIG. 2, Compound 9 induced a marked decrease in cellular ATP levels. Furthermore, this effect was reduced in the presence of high levels of glucose, suggesting that the decrease in ATP induced by Compound 9 could be compensated by glycolysis. This is similar to the discovery by the present inventors in methyl jasmonate (Fingrut et al., 2005). These data suggest a similarity between the mechanism of action of natural methyl jasmonate and its chemically novel derivative compound 9. Thus, it appears that a decrease in cellular energy levels can cause the cytotoxic effect of Compound 9.

(Example 5)
The ability of Compound 9 to reduce experimental metastasis of B16 melanoma cells to the lung in vivo The ability of Compound 9 to reduce experimental metastasis of B16 melanoma cells to the lung in vivo was determined.

Experimental setup The experiment consisted of 3 groups of C57b1 mice (12-15 weeks old, n = 12), all inoculated with B16F10 melanoma cells (B16F10 in 0.1 ml PBS × 1, inoculum 7 × 10 ⁵ Total cells / mouse). Group M1-untreated, Group M2-treated once daily with 5 days per week for 3 weeks with compound 9 in surfactant (10 mg / kg, diluted 1: 5 with saline, i.p. v.), and group M3-positive control group, treated with paclitaxel once every 7 days (15 mg / kg, iv). After 22 days, the mice were killed and the lungs were weighed. Metastatic lungs are heavier than normal lungs (which weigh approximately 200 mg), and the low lung weight compared to control tumor-bearing untreated mice shows an anti-metastatic effect. As can be seen in FIG. 3, compound 9 is very effective in suppressing metastasis to the lung, and by t-test, compound 9 vs. A P value of 0.000003 was obtained relative to the control. The data suggests that compound 9 is a very promising anticancer agent.

(Example 6)
Synthesis Examples of methods for synthesizing the prepared compounds of the present invention are described below.

Compound 9
To a solution of 8-hydroxyquinoline (620 mg, 4.27 mmol) and triethylamine (0.7 mL, 5.12 mmol) in dry THF (20 mL) with stirring at 0 ° C. under an argon atmosphere, jasmonyl chloride (900 mg, 3.94 mmol) in dry THF (20 mL) was added dropwise and the reaction mixture was stirred at 0 ° C. for 1.5 hours, warmed to room temperature and stirred for an additional hour. The solvent was then evaporated and the residue was diluted with CH ₂ Cl _{2 and} washed with saturated aqueous NaHCO ₃ (× 2). The organic layer was dried over MgSO ₄ and concentrated in vacuo. The residue was purified by VLC (EtOAc / petroleum ether 1: 9) to give compound 9 (728 mg, 55%) as a yellow oil.

Compound 11
A solution of anhydrous D-glucose (159 mg, 0.883 mmol) in pyridine (10 mL) was heated to 100 ° C. for 1 hour. Cool this solution to room temperature and add compound 9 (595 mg, 1.76 mmol) in pyridine (10 mL) and NaH (5 mg NaH in oil (60%), washed with petroleum ether before use, 0.132 mmol). It was. The reaction mixture was heated to 60 ° C. and stirred for 4 hours. The solvent was then evaporated and the residue was diluted with n- butanol _and extracted with K 3 PO ₄ aqueous solution (0.1 N). The organic layer was washed with water containing a few drops of AcOH and concentrated in vacuo. The residue was purified by VLC (EtOAc) to give compound 11 (45 mg, 14%) as a yellow oil.

  While particular embodiments of the present invention have been illustrated and described, it will be apparent that the invention is not limited to the embodiments described herein. Numerous modifications, changes, variations, substitutions and equivalents will be apparent to those skilled in the art without departing from the spirit and scope of the invention as set forth in the claims below.

The cytotoxicity by the increase in the density | concentration of the compound 9 (0.01-0.5 mM) in a lymphoblastic leukemia cell (Molt-4) and a peripheral blood leukocyte (PBL) is shown. Cytotoxicity (%) is plotted against compound concentration. The cytotoxicity by the concentration increase (0.01-0.5 mM) of the compound 11 in a lymphoblastic leukemia cell (Molt-4) and a peripheral blood leukocyte (PBL) is shown. Cytotoxicity (%) is plotted against compound concentration. FIG. 6 shows the ability of Compound 9 to induce a decrease in ATP levels in CT-26 colon cancer cells. The drop in ATP levels in the cells after 3 hours incubation in different media is plotted. High (28 mM) or Low (2 mM) glucose concentrations are plotted along with either low (0.2 mM) or high (0.5 mM) compound 9 concentrations. FIG. 5 shows the ability of Compound 9 to reduce experimental metastasis of B16 melanoma cells to the lung in vivo. Mice lung weights are plotted for a control group of untreated mice, a second group of mice treated with Compound 9, and a third group of mice treated with paclitaxel.

Claims (55)

Compounds represented by the structure of Formula I (including salts, hydrates, solvates, polymorphs, optical isomers, geometric isomers, enantiomers, diastereomers, and mixtures thereof):

[Where:
A is
a) COR ¹ ,
b) O-COR ¹⁰ and c) OR ¹¹
Selected from the group consisting of;
R ¹ is
a) heteroaryloxy,
_{b) -O [(CH 2)} p O)] m -R 12,
c) group of formula

D) when at least one of R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is haloalkyl, or R ⁵ and R ⁶ are attached to the carbon to which they are attached together _C 3 -C ₈ cycloalkyl, or forming a _C 3 -C ₈ cycloalkyl substituted with halo, ^{R 1} is further represent a hydrogen or an unsubstituted or substituted _C 1 _{-C 12} alkyl Can do;
R ² is hydrogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, OR ⁸ , oxo and NR ^9a R Selected from the group consisting of ^9b ;
R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₁ -C ₁₂ haloalkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or is selected from the group consisting of oR ^8, and ^NR 9a ^{R 9b,}
Alternatively, R ⁵ and R ⁶ together with the carbon to which they are attached form a C ₃ -C ₈ cycloalkyl, or a C ₃ -C ₈ cycloalkyl substituted with halo,
Alternatively, one of R ⁵ and R ⁶ represents an oxygen atom, and this oxygen atom is bonded to C ₆ to form a 6-membered or 5-membered oxygen-containing heterocyclic ring, respectively;
The bond between C ₉ and C ₁₀ may be a single bond or a double bond;
R ⁸ , R ^9a and R ^9b are each independently hydrogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted hetero R ^9a and R ^9b are selected from the group consisting of aryl, glucosyl, or together with the nitrogen to which they are attached, unsubstituted or substituted heterocycles or heteroaromatic rings (from O, N and S Optionally comprising one or more additional heteroatoms selected);
R ¹⁰ is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
R ¹¹ and R ¹² are each independently hydrogen or a hydroxy protecting group;
R ¹³ is a carboxy protecting group;
R ¹⁴ is a natural or non-natural amino acid residue;
n is selected from 0, 1 and 2;
m is an integer from 1 to 20; and p is an integer from 1 to 12.] The compound of claim ¹ , wherein A is COR ¹ . The compound of claim 2, wherein R ¹ is heteroaryloxy. 4. A compound according to claim 3, wherein R < ¹ > is quinolinyloxy. The compound according to claim 2, wherein R ¹ is —O [(CH ₂ ) ₂ O)] ₄ —R ¹² . 6. A compound according to claim 5, wherein R ¹² is hydrogen or a trialkylsilylhydroxy protecting group. R ¹ is represented by the following formula:

The compound of Claim 2 which is group of these. R ¹³ is ^{methyl, R 14} is a leucine residue, compound of Claim 7. R ⁵ and R ^6, together with the carbon to which they are attached form a C ₃ -C ₈ cycloalkyl substituted by halo, A compound according to claim 1. The compound of claim 1, wherein A is O—COR ¹⁰ and R ¹⁰ is unsubstituted or substituted C ₁ -C ₁₂ alkyl. The compound according to claim 1, wherein A is OR ¹¹ and R ¹¹ is hydrogen or a trialkylsilylhydroxy protecting group. The compound of claim 1, wherein R ² is oxo. A bond is a double bond between C ₉ and _{^{C 10, R 3, R 4}} , R 5, ^{R 6,} and ^{R 7} are hydrogen, A compound according to claim 1. The compound according to claim 1, wherein R ⁶ represents an oxygen atom, and the oxygen atom is bonded to C ₆ to form an oxygen-containing 5-membered heterocyclic ring. The compound is

2. The compound of claim 1 selected from the group consisting of:   A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 as an active ingredient.   A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 15 as an active ingredient.   The pharmaceutical composition according to claim 16, which is in a form suitable for oral administration.   The pharmaceutical composition according to claim 16, which is in a form suitable for oral administration, intravenous administration by injection, topical administration, administration by inhalation, or administration by suppository.   A method for inhibiting cancer cell growth, comprising contacting a cancer cell with a therapeutically effective amount of the compound of claim 1.   A method for inhibiting cancer cell growth comprising contacting a cancer cell with a therapeutically effective amount of a compound of claim 15.   21. The method of claim 20, wherein the cancer is a mammalian cancer.   24. The method of claim 22, wherein the mammal is a human.   Cancer is lymphoproliferative disease, breast cancer, ovarian cancer, prostate cancer, cervical cancer, endometrial cancer, bone cancer, liver cancer, stomach cancer, colon cancer, pancreatic cancer, thyroid cancer, head and neck cancer, central nervous system cancer 21. The method of claim 20, selected from the group consisting of: cancer of the peripheral nervous system, skin cancer, kidney cancer, and all these metastases.   Cancer is hepatocellular carcinoma, liver cancer, hepatoblastoma, rhabdomyosarcoma, esophageal cancer, thyroid cancer, ganglioblastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, blood vessel Sarcoma, endothelial sarcoma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma (highly differentiated, moderately differentiated, poorly differentiated or Undifferentiated), renal cell carcinoma, adrenal gland, adrenal-like adenocarcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, fetal cancer, Wilms tumor, testicular tumor, lung cancer (including small cell, non-small cell and large cell lung cancer) ), Bladder cancer, glioma, astrocytoma, medulloblastoma, craniopharynoma, ependymoma, pineal tumor, retinoblastoma, neuroblastoma, colon cancer, rectal cancer, hematopoietic malignancy ( Acute myeloid leukemia, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mast cell white blood , Multiple myeloma, spinal lymphoma, Hodgkin's lymphoma, including non-Hodgkin's lymphoma is selected from the group consisting Included) all types of leukemias and lymphomas, The method of claim 20.   Cancer is from the group consisting of prostate cancer, breast cancer, skin cancer, colon cancer, lung cancer, pancreatic cancer, lymphoma, myeloma, leukemia, head and neck cancer, kidney cancer, stomach cancer, ovarian cancer, bone cancer, liver cancer or thyroid cancer 21. The method of claim 20, wherein the method is selected.   21. The method of claim 20, wherein the cancer is selected from leukemia (including lymphoblastic leukemia), lung cancer, melanoma, kidney cancer, gastric cancer, and colon cancer.   A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim 1.   16. A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim 15.   30. The method of claim 28, wherein the subject is a mammal.   32. The method of claim 30, wherein the subject is a human.   Cancer is lymphoproliferative disease, breast cancer, ovarian cancer, prostate cancer, cervical cancer, endometrial cancer, bone cancer, liver cancer, stomach cancer, colon cancer, pancreatic cancer, thyroid cancer, head and neck cancer, central nervous system cancer 30. The method of claim 28, selected from the group consisting of cancer of the peripheral nervous system, skin cancer, kidney cancer, and all these metastases.   Cancer is hepatocellular carcinoma, liver cancer, hepatoblastoma, rhabdomyosarcoma, esophageal cancer, thyroid cancer, ganglioblastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, blood vessel Sarcoma, endothelial sarcoma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma (highly differentiated, moderately differentiated, poorly differentiated or Undifferentiated), renal cell carcinoma, adrenal gland, adrenal-like adenocarcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, fetal cancer, Wilms tumor, testicular tumor, lung cancer (including small cell, non-small cell and large cell lung cancer) ), Bladder cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, retinoblastoma, neuroblastoma, colon cancer, rectal cancer, hematopoietic malignancy ( Acute myeloid leukemia, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mast cell white blood , Multiple myeloma, spinal lymphoma, Hodgkin's lymphoma, including non-Hodgkin's lymphoma is selected from the group consisting Included) all types of leukemias and lymphomas, The method of claim 28.   Cancer is from the group consisting of prostate cancer, breast cancer, skin cancer, colon cancer, lung cancer, pancreatic cancer, lymphoma, myeloma, leukemia, head and neck cancer, kidney cancer, stomach cancer, ovarian cancer, bone cancer, liver cancer or thyroid cancer 30. The method of claim 28, wherein the method is selected.   30. The method of claim 28, wherein the cancer is selected from leukemia (including lymphoblastic leukemia), lung cancer, melanoma, kidney cancer, stomach cancer, and colon cancer. Compounds of formula I in the preparation of therapeutic agents useful for the treatment of cancer, including salts, hydrates, solvates, polymorphs, optical isomers, geometric isomers, enantiomers, diastereomers, and mixtures thereof Use of:

[Where:
A is
a) COR ¹ ,
b) O-COR ¹⁰ and c) OR ¹¹
Selected from the group consisting of;
R ¹ is
a) heteroaryloxy,
_{b) -O [(CH 2)} p O)] m -R 12,
c) group of formula

D) when at least one of R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is haloalkyl, or R ⁵ and R ⁶ are attached to the carbon to which they are attached together _C 3 -C ₈ cycloalkyl, or forming a _C 3 -C ₈ cycloalkyl substituted with halo, ^{R 1} is further represent a hydrogen or an unsubstituted or substituted _C 1 _{-C 12} alkyl Can do;
R ² is hydrogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, OR ⁸ , oxo and NR ^9a R Selected from the group consisting of ^9b ;
R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₁ -C ₁₂ haloalkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or is selected from the group consisting of oR ^8, and ^NR 9a ^{R 9b,}
Alternatively, R ⁵ and R ⁶ together with the carbon to which they are attached form a C ₃ -C ₈ cycloalkyl, or a C ₃ -C ₈ cycloalkyl substituted with halo,
Alternatively, one of R ⁵ and R ⁶ represents an oxygen atom, and this oxygen atom is bonded to C ₆ to form a 6-membered or 5-membered oxygen-containing heterocyclic ring, respectively;
The bond between C ₉ and C ₁₀ may be a single bond or a double bond;
R ⁸ , R ^9a and R ^9b are each independently hydrogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted hetero R ^9a and R ^9b are selected from the group consisting of aryl, glucosyl, or together with the nitrogen to which they are attached, unsubstituted or substituted heterocycles or heteroaromatic rings (from O, N and S) Optionally comprising one or more additional heteroatoms selected);
R ¹⁰ is selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₁₂ alkyl, unsubstituted or substituted C ₃ -C ₈ cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
R ¹¹ and R ¹² are each independently hydrogen or a hydroxy protecting group;
R ¹³ is a carboxy protecting group;
R ¹⁴ is a natural or non-natural amino acid residue;
n is selected from 0, 1 and 2;
m is an integer from 1 to 20; and p is an integer from 1 to 12.] Compounds represented by the structure of Formula 11 (including salts, hydrates, solvates, polymorphs, optical isomers, geometric isomers, enantiomers, diastereomers, and mixtures thereof):

  A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 37 as an active ingredient.   40. The pharmaceutical composition according to claim 38, wherein the composition is in a form suitable for oral administration.   39. The pharmaceutical composition according to claim 38, in a form suitable for oral administration, intravenous administration by infusion, topical administration, administration by inhalation, or administration by suppository.   38. A method for inhibiting cancer cell growth comprising contacting a cancer cell with a therapeutically effective amount of a compound of claim 37.   42. The method of claim 41, wherein the cancer is a mammalian cancer.   43. The method of claim 42, wherein the mammal is a human.   Cancer is lymphoproliferative disease, breast cancer, ovarian cancer, prostate cancer, cervical cancer, endometrial cancer, bone cancer, liver cancer, stomach cancer, colon cancer, pancreatic cancer, thyroid cancer, head and neck cancer, central nervous system cancer 42. The method of claim 41, selected from the group consisting of cancer of the peripheral nervous system, skin cancer, kidney cancer, and all these metastases.   Cancer is hepatocellular carcinoma, liver cancer, hepatoblastoma, rhabdomyosarcoma, esophageal cancer, thyroid cancer, ganglioblastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, blood vessel Sarcoma, endothelial sarcoma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma (highly differentiated, moderately differentiated, poorly differentiated or Undifferentiated), renal cell carcinoma, adrenal gland, adrenal-like adenocarcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, fetal cancer, Wilms tumor, testicular tumor, lung cancer (including small cell, non-small cell and large cell lung cancer) ), Bladder cancer, glioma, astrocytoma, medulloblastoma, craniopharynoma, ependymoma, pineal tumor, retinoblastoma, neuroblastoma, colon cancer, rectal cancer, hematopoietic malignancy ( Acute myeloid leukemia, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mast cell white blood , Multiple myeloma, spinal lymphoma, Hodgkin's lymphoma, including non-Hodgkin's lymphoma is selected from the group consisting Included) all types of leukemias and lymphomas, The method of claim 41.   Cancer is from the group consisting of prostate cancer, breast cancer, skin cancer, colon cancer, lung cancer, pancreatic cancer, lymphoma, myeloma, leukemia, head and neck cancer, kidney cancer, stomach cancer, ovarian cancer, bone cancer, liver cancer or thyroid cancer 42. The method of claim 41, wherein the method is selected.   42. The method of claim 41, wherein the cancer is selected from leukemia (including lymphoblastic leukemia), lung cancer, melanoma, kidney cancer, stomach cancer, and colon cancer.   38. A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim 37.   49. The method of claim 48, wherein the subject is a mammal.   50. The method of claim 49, wherein the subject is a human.   Cancer is lymphoproliferative disease, breast cancer, ovarian cancer, prostate cancer, cervical cancer, endometrial cancer, bone cancer, liver cancer, stomach cancer, colon cancer, pancreatic cancer, thyroid cancer, head and neck cancer, central nervous system cancer 49. The method of claim 48, selected from the group consisting of cancer of the peripheral nervous system, skin cancer, kidney cancer, and all these metastases.   Cancer is hepatocellular carcinoma, liver cancer, hepatoblastoma, rhabdomyosarcoma, esophageal cancer, thyroid cancer, ganglioblastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, blood vessel Sarcoma, endothelial sarcoma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma (highly differentiated, moderately differentiated, poorly differentiated or Undifferentiated), renal cell carcinoma, adrenal gland, adrenal-like adenocarcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, fetal cancer, Wilms tumor, testicular tumor, lung cancer (including small cell, non-small cell and large cell lung cancer) ), Bladder cancer, glioma, astrocytoma, medulloblastoma, craniopharynoma, ependymoma, pineal tumor, retinoblastoma, neuroblastoma, colon cancer, rectal cancer, hematopoietic malignancy ( Acute myeloid leukemia, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mast cell white blood , Multiple myeloma, spinal lymphoma, Hodgkin's lymphoma, including non-Hodgkin's lymphoma is selected from the group consisting Included) all types of leukemias and lymphomas, The method of claim 48.   Cancer is from the group consisting of prostate cancer, breast cancer, skin cancer, colon cancer, lung cancer, pancreatic cancer, lymphoma, myeloma, leukemia, head and neck cancer, kidney cancer, stomach cancer, ovarian cancer, bone cancer, liver cancer or thyroid cancer 49. The method of claim 48, wherein the method is selected.   49. The method of claim 48, wherein the cancer is selected from leukemia (including lymphoblastic leukemia), lung cancer, melanoma, kidney cancer, stomach cancer, and colon cancer. Compounds of formula 11 (including salts, hydrates, solvates, polymorphs, optical isomers, geometric isomers, enantiomers, diastereomers, and mixtures thereof) in the preparation of therapeutic agents useful for the treatment of cancer Use of:

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